PERSPECTIVES ON VALUE 961 The effectiveness and value of bempedoic acid and inclisiran for heterozygous familial hypercholesterolemia and secondary prevention of ASCVD A summary from the Institute for Clinical and Economic Review’s Midwest Comparative Effectiveness Public Advisory Council Foluso Agboola, MBBS, MPH; Grace A Lin, MD, MAS; Dhruv S Kazi, MD, MSc, MS; Avery McKenna; and Steven D Pearson, MD, MSc Atherosclerotic cardiovascular dis- necessary, a proprotein convertase ease (ASCVD) encompasses a set of subtilisin/kexin type 9 (PCSK9) inhib- Author affiliations 9 chronic conditions that includes coro- itor is recommended. Foluso Agboola, MBBS, MPH; Avery nary artery disease, peripheral artery A new option for lowering choles- McKenna; and Steven D Pearson, MD, disease, cerebrovascular disease, and terol is bempedoic acid (combined MSc, Institute for Clinical and Economic aortic atherosclerotic disease. In the with ezetimibe [Nexlizet] or with- Review, Boston, MA. Grace A Lin, MD, United States, ASCVD affects approxi- out ezetimibe [Nexletol], Esperion MAS, Division of General Internal mately 1 in 10 people; represents a high Therapeutics, Inc.), which was Medicine and Philip R. Lee Institute risk for future major adverse cardio- approved by the US Food and Drug for Health Policy Studies, University of California, San Francisco. Dhruv S Kazi, vascular events (MACE), such as heart Administration (FDA) in February MD, MSc, MS, Smith Center for Outcomes attacks and strokes; and is the leading 2020. Bempedoic acid is an inhibitor of Research in Cardiology, Beth Israel 1,2 cause of death. adenosine triphosphate (ATP) citrate Deaconess Medical Center and Harvard Heterozygous familial hypercholes- lyase that lowers LDL-C by reduc- Medical School, Boston, MA. terolemia (HeFH) and other conditions ing cholesterol synthesis upstream of that cause very high levels of low- HMG Co-A reductase (statins) and up- AUTHOR CORRESPONDENCE: Foluso Agboola, [email protected] density lipoprotein cholesterol regulating LDL receptors.10 Another (LDL-C) are associated with a high new lipid-lowering agent, inclisiran risk of premature ASCVD and MACE.3 (Novartis), is currently under FDA Although HeFH is relatively com- review. Inclisiran is a double-stranded J Manag Care Spec Pharm. mon—affecting approximately 1 in 250 small interfering RNA agent that low- 2021;27(7):961-66 people in the United States—several ers cholesterol through targeting and Copyright © 2021, Academy of Managed studies have reported that the con- inhibiting hepatic PCSK9 synthesis.11 Care Pharmacy. All rights reserved. dition is still underdiagnosed and The Institute for Clinical and undertreated, particularly among Economic Review (ICER) conducted women, Blacks, and Asians.4-6 a systematic literature review LDL-C reduction is mainly achieved and cost-effectiveness analysis to meeting of the Midwest Comparative by high dose or maximally tolerated evaluate the health and economic Effectiveness Public Advisory Council statin therapy.7,8 For patients who con- outcomes of bempedoic acid and on February 5, 2021. The detailed tinue to have LDL-C levels at or above inclisiran. In this report, we pres- report is available at https://icer. 70 mg/dL, the addition of ezetimibe is ent the summary of our findings and org/wp-content/uploads/2020/10/ recommended as second-line therapy, highlight the policy discussion with ICER_High-Cholesterol_Final- and if further LDL-C reduction is key stakeholders held at a public Evidence-Report_030221.pdf. Vol. 27, No. 7 | July 2021 | JMCP.org The effectiveness and value of bempedoic acid and inclisiran for heterozygous 962 familial hypercholesterolemia and secondary prevention of ASCVD in extremity, muscle spasms, and tendon rupture); hyper- Summary of Findings uricemia; gout; elevated liver enzymes (ALTand AST); and CLINICAL EFFECTIVENESS changes in renal laboratory parameters (eg, glomerular We conducted pairwise meta-analyses on each drug sep- filtration rate and blood creatinine level). arately. We did not attempt to compare these treatments Inclisiran. We identified three phase 3 RCTs of inclisiran vs with each other because of key differences across trials in placebo, 2 of which were conducted in patients with estab- patient characteristics and trial design. Additionally, we did lished ASCVD or ASCVD risk equivalent16 and 1 in patients not pursue a quantitative indirect comparison of inclisiran with HeFH.11 All patients were on maximally tolerated lipid- with PCSK9 inhibitors because trials evaluating the impact lowering therapy. of inclisiran on cardiovascular outcomes have not been Meta-analyses of the 3 RCTs (N = 3,660) showed that completed. inclisiran therapy decreased LDL-C levels by 51% from Bempedoic Acid. We identified 5 pivotal phase 3 random- baseline (mean difference = −50.5, 95% CI = −45.5 to −55.5) ized clinical trials (RCTs) of bempedoic acid with or without compared with placebo after 77 weeks of treatment.11,16 A ezetimibe.10,12-15 Four studies examined bempedoic acid vs similar level of LDL-C reduction was observed in the study placebo, including 2 RCTs in patients with ASCVD or HeFH conducted exclusively in patients with HeFH (N = 482).11 who required further LDL-C lowering despite being on Inclisiran also improved other lipid parameters compared maximally tolerated statin therapy10,14 and 2 RCTs in patients with placebo, including an increase in HDL cholesterol and with ASCVD, HeFH, or hypercholesterolemia who were reductions in PCSK9, total cholesterol, non-HDL choles- deemed to be statin intolerant, defined as the inability to terol, apolipoprotein B, and lipoprotein(a). Clinical outcome tolerate trials of at least 2 statins.12,15 The fifth RCT examined studies of inclisiran are also ongoing. Meta-analysis of pre- the combination pill bempedoic acid/ezetimibe vs bempe- specified exploratory cardiovascular endpoints reported doic acid alone, ezetimibe alone, and placebo in patients in the phase 3 trials showed a lower rate of the composite with ASCVD, HeFH, or with multiple risk factors for cardio- cardiovascular outcome (cardiovascular mortality, cardiac vascular disease while on maximally tolerated statins.13 arrest, non-fatal myocardial infarction, or stroke) with Meta-analyses of the 5 RCTs (N = 3,924) showed that inclisiran compared with placebo (RR = 0.76; 95% CI = 0.60- bempedoic acid provided an overall 19.5% decrease in 0.96).11,16 The rates of cardiovascular death and all-cause LDL-C after 12 weeks of treatment (I2 = 69%, P < 0.01) com- mortality were similar between treatment arms. pared with placebo.10,12-15 In patients with statin intolerance Overall, a similar incidence of AEs, serious AEs, and (N = 614), a larger LDL-C reduction was observed with discontinuation were observed between treatment groups. bempedoic acid compared with placebo (24.6% vs 17.7%; The most common AE with inclisiran was injection site test for subgroup difference, P = 0.05).12,15 Bempedoic acid reaction, which occurred in 5.4% of patients vs 0.8% in the also improved other lipid parameters, including significant placebo group.11,16 reductions vs placebo in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and high- LIMITATIONS OF CLINICAL EFFECTIVENESS sensitivity C-reactive protein. Two of the RCTs presented Efficacy data on bempedoic acid and inclisiran are limited to data on cardiovascular events and mortality at 52 weeks.10,14 short-term LDL reduction; long-term effect on clinical out- Meta-analyses of these studies for these endpoints found comes has yet to be established for either drug. Bempedoic relative risks above 1 for all-cause mortality (rate ratio acid blocks cholesterol synthesis upstream of statins, but it [RR] = 2.25; 95% CI = 0.76-6.67) and cardiovascular mortality remains to be seen whether the degree of LDL-C lowering (RR = 1.52; 95% CI = 0.41-5.70), but these studies were not observed will translate into a similar degree of reduction in powered to examine these endpoints, and numbers of MACE rates as statin drugs. Additionally, bempedoic acid's patients with these outcomes were very small.10,14 Larger safety profile raises important questions about whether ongoing clinical outcome studies will assess these out- the increased risk of hyperuricemia and gout, as well as a comes to evaluate fully how the reduction in LDL-C with risk of tendon rupture, seen in the RCTs will be important bempedoic acid translates into patient-centered outcomes. real-world problems. For inclisiran, although the degree of Data on adverse events (AEs) from existing trials show LDL-C lowering appears to be in the same general range as that more AEs were associated with bempedoic acid than found for PCSK9 inhibitors, whose mechanism of action lies placebo (24.1% vs 20.3%, P = 0.01).10,12,14,15 AEs that occurred along the same biochemical pathway, there remains uncer- with more frequency in the bempedoic acid group than tainty whether this will translate into a reduction in MACE the placebo group were muscle-related events (eg, pain rates that are more comparable to those seen with PCSK9 JMCP.org | July 2021 | Vol. 27, No. 7 The effectiveness and value of bempedoic acid and inclisiran for heterozygous 963 familial hypercholesterolemia and secondary prevention of ASCVD TABLE 1 Incremental Cost-Effectiveness Ratios Compared with Maximally Tolerated Lipid-Lowering Therapy for the Base Case Treatment Cost per Cost per Cost per Cost per (compared with statin + ezetimibe) QALY gained, $ evLYG, $ LY gained, $ MACE averted, $ Inclisirana + s t atin + e zetimib e $157,000 $142,000 $147,000 $451,000 Bempedoic acid + ezetimibe + statin $186,000 $168,000 $175,000 $535,000 aWe used a hypothetical annual placeholder price of $5,644 based on equivalent pricing to PCSK9 inhibitor drugs from the Federal Supply Schedule as of September 1, 2020, and assuming 2 doses per year. Initial treatment year requires 3 doses. evLYG = equal value per life-years gained; LY = life-year; MACE = major adverse cardiovascular events; QALY = quality-adjusted life-year.